Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cyclic adenosine 3':5'-monophosphate (cyclic AMP) metabolism of stratified normal rat urothelium propagated in vitro on a floating collagen matrix was characterized and used as a basis for identifying potential biochemical lesions in tumorigenic cell lines. The four neoplastic urothelial cell types studied (AY-27, AY-32, AY-33, and AY-34) were derived from Fischer 344 rats fed the carcinogen N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide. Epinephrine or prostaglandin E1 caused a rise in the cyclic AMP content of normal cultures which was potentiated in the presence of the cyclic nucleotide phosphodiesterase inhibitor 1-methyl-3-isobutylxanthine or by forskolin, a diterpene activator of adenylate cyclase in intact cells. The expected, normal profile of cyclic AMP accumulation in response to beta-adrenergic receptor agonists was epinephrine greater than norepinephrine greater than phenylephrine. By every measure, the tumorigenic AY-27 cells demonstrated an overall decrease of functional adenylate cyclase activity. This was evidenced most by the low accumulation of cyclic AMP observed in response to forskolin. While prostaglandin E1 elicited a heightened cyclic AMP level in these cells, their vanishingly low response to catecholamines also suggested a potential lack of functional beta-adrenergic receptors. Cyclic AMP phosphodiesterase activity was elevated in soluble enzyme preparations obtained from cultures of AY-27 cells. Observations of AY-32 cells were diametrically opposite to the findings with AY-27 cells. In AY-32 cells, prostaglandin E1 receptors appeared to be functionally absent. The beta-adrenergic receptor agonist response profile was abnormal in AY-32 cells. Norepinephrine produced a greater accumulation of cyclic AMP than epinephrine, and phenylephrine stimulated a much greater than normal response. Forskolin stimulation indicated an average level of adenylate cyclase activity in AY-32 cultures. Soluble preparations from AY-32 cells demonstrated a normal amount of cyclic AMP phosphodiesterase activity. AY-33 cells were comparable to normal urothelial cells in all respects save one. These tumorigenic cells had elevated levels of cyclic AMP phosphodiesterase activity. AY-34 cells, like AY-32 cells, were deficient in their responsiveness to prostaglandin E1. However, unlike the other tumorigenic lines, AY-34 cells had an excess of adenylate cyclase as demonstrated by their extraordinary responsiveness to forskolin. In addition, the accumulation of cyclic AMP in AY-34 cells in response to stimulation by epinephrine and norepinephrine, but not phenylephrine, was unusually great.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Aberrant cyclic adenosine 3':5'-monophosphate metabolism in cultures of tumorigenic rat urothelium. 298 Nov 57

The effect on lactose production of several external modulators of intracellular cyclic AMP was studied in rat mammary gland tissue slices and explants. Adrenaline, a beta-adrenergic receptor effector, forskolin, a direct adenylate cyclase activator and fluphenazine, a calmodulin inhibitor, all produced an increase in the intracellular level of cyclic AMP and a concomitant inhibition of lactose production. These results suggest a role for adrenaline and calmodulin in modulating cyclic AMP levels in mammary tissue during the lactogenic cycle.
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PMID:A role for adrenaline and calmodulin in modulating cyclic AMP levels during the lactogenic cycle. 299 Oct 6

Intravitreal injection of ouabain was used to induce unilateral hypotony and to study the relationship of adenylate cyclase (AC) and sodium-potassium activated adenosine triphosphatase (NaK-ATPase) both of which are involved in the production of aqueous humour. After preliminary experiments, days 3 and 5 were chosen as representative times when IOP was maximally reduced and stable following ouabain injection. NaK-ATPase and adenylate cyclase activities were measured biochemically in the same homogenates of isolated ciliary processes (CP). Biochemical measurements showed that 46% of NaK-ATPase activity was inhibited after 3 days, and about 78% of NaK-ATPase was inhibited 5 days after ouabain injection. At the beginning of NaK-ATPase inhibition there was a significant stimulation of adenylate cyclase activity of the CP. The highest activities were seen 2 and 3 days after ouabain injection. The suggestion is made that these 2 enzymes are interdependent.
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PMID:Stimulation of adenylate cyclase of ciliary processes in response to decreased inflow of aqueous humour. 299 86

Effects of exogenous prostaglandin E2 (PGE2) on rates of lipolysis in sections of subcutaneous adipose tissue biopsied from fed and fasted Holstein steers were determined. The interaction of PGE2 with several exogenous effectors of lipolysis and of the adenylate cyclase-cAMP system also was measured. Epinephrine increased basal (nonstimulated) lipolysis approximately one-fold. Prostaglandin E2 had no effect on either basal or epinephrine-stimulated lipolysis. Dibutyryl cAMP increased rate of lipolysis .4-fold, whereas theophylline increased lipolysis more than one-fold. Theophylline had an additive effect on epinephrine-stimulated lipolysis. Dibutyryl cAMP increased theophylline-stimulated lipolysis but not epinephrine-stimulated lipolysis. Prostaglandin E2 had no effect on epinephrine-, dibutyryl cAMP- or theophylline-stimulated lipolysis. Fasting decreased basal lipolysis by 40%. Furthermore, lipolysis in tissue incubated with PGE2, epinephrine or PGE2 plus epinephrine decreased from 30 to 50% upon fasting. As also shown with tissue from fed steers, PGE2 did not alter basal or epinephrine-stimulated lipolysis in tissue from fasted steers. Influences of exogenous effectors on lipolysis in adipose tissue from fed and fasted steers indicate that PGE2 does not control the adenylate cyclase-cAMP system that regulates lipolysis in bovine adipose tissue.
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PMID:Evaluation of prostaglandin E2 as a regulator of lipolysis in bovine adipose tissue. 300 20

Acute hormonal regulation of liver carbohydrate metabolism mainly involves changes in the cytosolic levels of cAMP and Ca2+. Epinephrine, acting through beta 2-adrenergic receptors, and glucagon activate adenylate cyclase in the liver plasma membrane through a mechanism involving a guanine nucleotide-binding protein that is stimulatory to the enzyme. The resulting accumulation of cAMP leads to activation of cAMP-dependent protein kinase, which, in turn, phosphorylates many intracellular enzymes involved in the regulation of glycogen metabolism, gluconeogenesis, and glycolysis. These are (1) phosphorylase b kinase, which is activated and, in turn, phosphorylates and activates phosphorylase, the rate-limiting enzyme for glycogen breakdown; (2) glycogen synthase, which is inactivated and is rate-controlling for glycogen synthesis; (3) pyruvate kinase, which is inactivated and is an important regulatory enzyme for glycolysis; and (4) the 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase bifunctional enzyme, phosphorylation of which leads to decreased formation of fructose 2,6-P2, which is an activator of 6-phosphofructo-1-kinase and an inhibitor of fructose 1,6-bisphosphatase, both of which are important regulatory enzymes for glycolysis and gluconeogenesis. In addition to rapid effects of glucagon and beta-adrenergic agonists to increase hepatic glucose output by stimulating glycogenolysis and gluconeogenesis and inhibiting glycogen synthesis and glycolysis, these agents produce longer-term stimulatory effects on gluconeogenesis through altered synthesis of certain enzymes of gluconeogenesis/glycolysis and amino acid metabolism. For example, P-enolpyruvate carboxykinase is induced through an effect at the level of transcription mediated by cAMP-dependent protein kinase. Tyrosine amino-transferase, serine dehydratase, tryptophan oxygenase, and glucokinase are also regulated by cAMP, in part at the level of specific messenger RNA synthesis. The sympathetic nervous system and its neurohumoral agonists epinephrine and norepinephrine also rapidly alter hepatic glycogen metabolism and gluconeogenesis acting through alpha 1-adrenergic receptors. The primary response to these agonists is the phosphodiesterase-mediated breakdown of the plasma membrane polyphosphoinositide phosphatidylinositol 4,5-P2 to inositol 1,4,5-P3 and 1,2-diacylglycerol. This involves a guanine nucleotide-binding protein that is different from those involved in the regulation of adenylate cyclase. Inositol 1,4,5-P3 acts as an intracellular messenger for Ca2+ mobilization by releasing Ca2+ from the endoplasmic reticulum.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mechanisms of hormonal regulation of hepatic glucose metabolism. 303 41

The effects of insulin, forskolin, isoproterenol, and epinephrine on 3-O-methylglucose (hexose) transport and cell cyclic AMP levels were determined in adult rat cardiomyocytes. Insulin stimulated hexose transport in these cells an average of 2.5-fold. Initial hexose transport rates at 1 mM hexose were 3.75 X 10(-2) nmol/mg cell protein/second in the absence of insulin, and 8.25 X 10(-2) nmol/mg cell protein/second in the presence of 12.3 microM insulin. Forskolin at 5 microM nearly abolished hexose transport within 3 s of exposure, but did not increase cell cyclic AMP concentrations within 9 s. The apparent Ki for hexose transport inhibition was about 0.3 microM forskolin. Epinephrine and isoproterenol at 50 microM increased cell cyclic AMP 4-fold during 9 s exposure, but did not affect hexose transport. Treatment of cells with these catecholamines of forskolin for up to 99 s increased cell cyclic AMP, but only forskolin inhibited hexose transport. We conclude from these results that forskolin acts on hexose transport independent of its action on adenyl cyclase, and that cyclic AMP does not inhibit or stimulate hexose transport.
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PMID:Forskolin inhibition of hexose transport in cardiomyocytes. 303 51

The voltage dependence of the intracellular Ca2+ transients was measured in single rat ventricular myocytes with the fluorescent Ca2+ indicator dye fura-2. The whole-cell voltage clamp technique was used to measure the membrane current, and 0.9 mM fura-2 was loaded into the cell by including it in the dialyzing solution of the patch electrode. A mechanical light chopper operating at 1200 Hz was used to obtain simultaneous measurements of the intracellular Ca2+ activity with fluorescence excitation on either side of the isosbestic point (330 nm and 410 nm). The symmetry of the two optical Ca2+ signals was used as a criterion to guard against artifacts resulting, for instance, from motion. The voltage dependence of peak Ca2+ current and the Ca2+ transient measured 25 ms after depolarizing clamps from a holding potential of -40 mV were bell-shaped and virtually identical. The Ca2+ entry estimated from the integral of the Ca2+ current (0 mV, 25 ms) corresponds to a 5-10 microM increase in the total intracellular Ca2+ concentration, whereas the optical signal indicated a 100 microM increase in total intracellular Ca2+. Repolarization of clamp pulses from highly positive potentials were accompanied by a second Ca2+ transient, the magnitude of which, when summed with that measured during depolarization, was nearly constant. Ryanodine (10 microM) had little or no effect on the peak Ca2+ current but reduced the magnitude of the early Ca2+ transients by 70-90%. Epinephrine (1 microM) increased the Ca2+ current and the Ca2+ transients, accelerated the rate of decline of the Ca2+ transients at potentials between -30 and +70 mV, and reduced the intracellular [Ca2+] below baseline at potentials positive to +80 or negative to -40 mV, where clamp pulses did not elicit any Ca2+ release. Elevation of intracellular cAMP mimicked the relaxant effect of epinephrine at depolarizing potentials, whereas elevation of extracellular [Ca2+] did not. These results suggest that most of the activator Ca2+ in rat ventricular cells is released from the sarcoplasmic reticulum as a graded response to sarcolemmal Ca2+ influx. Consistent with a graded Ca2+-induced Ca2+ release we find that epinephrine increases the internal Ca2+ release by increasing the Ca2+ current. Epinephrine may also increase the Ca2+ content of the sarcoplasmic reticulum that may, in turn, increase the Ca2+-induced Ca2+ release. The relaxant effect of epinephrine appears to be caused by enhanced rate of Ca2+ resequestration and is mediated by adenylate cyclase system.
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PMID:Epinephrine enhances Ca2+ current-regulated Ca2+ release and Ca2+ reuptake in rat ventricular myocytes. 316 23

Vasoconstrictor responses to prostaglandin F2 alpha and noradrenaline were investigated in ring segments of feline femoral, coronary and cerebral arteries incubated in calcium-free solutions containing different concentrations of magnesium (1.2, 4.4 and 13.2 mM). Contractions produced by prostaglandin F2 alpha and noradrenaline were depressed when calcium was omitted from the incubation solution. The presence of raised concentrations of magnesium (4.4 or 13.2 mM) in the tissue bath further depressed the prostaglandin F2 alpha and noradrenaline contractions in calcium-free medium. In a separate set of experiments the vessel wall contents of cAMP and cGMP were measured before and after the additions of 4.4 or 13.2 mM magnesium; stable relaxations by magnesium were noted but there was no parallel change in the vessel content of cAMP or cGMP. The results indicate that magnesium may interfere with the release of calcium from intracellular depots, and that neither adenylate cyclase, nor guanylate cyclase are involved in the dilator activity of magnesium in isolated arteries.
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PMID:The influence of magnesium on the release of calcium from intracellular depots in vascular smooth muscle cells. 316 68

Known synergism between forskolin and hormones in adenylate cyclase activation leads to the supposition that hormone might stimulate forskolin binding. That possibility was tested using intact wild type S49 cultured lymphoma cells. Using 40 nM [3H]-forskolin it was shown that the extent of forskolin binding using a filtration technique increased with the concentration of epinephrine or isoproterenol (INE). Moreover, the hormone-dependent forskolin binding was stereospecific (requiring l- rather than d-epinephrine), it was not observed in the cyc- variant and it was not inhibited by cytochalasin B. These observations lead to the conclusion that the binding is specifically associated with the adenylate cyclase system and requires a functional Gs unit. Epinephrine-stimulated forskolin binding did not correlate exactly with forskolin activation of adenylate cyclase in the presence of similar concentrations of epinephrine. It was concluded from that observation that there is not a one to one correspondence between binding and activation.
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PMID:Forskolin binding to intact S49 lymphoma cells. 319 76

1. The effects of adrenaline, isoprenaline and forskolin upon the evoked contractions of field-stimulated preparations of human, pregnant, isolated myometrium have been examined. Specimens were obtained at lower segment Caesarean section from patients at 31 (n = 1) and 36-40 (n = 10) weeks of gestation. 2. Adrenaline enhanced the electrically evoked contractions of all preparations studied, indicating that its predominant action on these pregnant myometrial tissues was at alpha- and not beta-adrenoceptors. 3. Isoprenaline in concentrations at and below 10 mumol/l produced inhibitory effects in eight of 11 experiments. In the remaining three experiments, tissues were not responsive to the inhibitory effects of isoprenaline. 4. In all preparations exposed to higher concentrations of isoprenaline (30 or 100 mumol/l), its effects were excitatory. 5. Forskolin produced inhibitory effects on preparations from all uteri, including those from which tissues unresponsive to isoprenaline had been obtained. 6. It is suggested that forskolin in the concentrations which were effective in this study produced its inhibitory effects largely through activation of adenylate cyclase. This implies that the lack of an inhibitory response of some preparations to isoprenaline was not due to reduced activity of the adenylate cyclase system, but that the failure of isoprenaline to produce an inhibitory effect could be due to diminished numbers of beta-adrenoceptors and/or increased numbers of alpha-adrenoceptors, or to a defect in the coupling of the receptors to the adenylate cyclase system. Alternatively, the presence of an endogenous antagonist of the effects of isoprenaline (for example, an eicosanoid), could mask its inhibitory effects. 7. The absence of an inhibitory effect of isoprenaline on some specimens of human gravid myometrium could have clinical implications, in view of the widespread use of beta 2-adrenoceptor agonists as uterine relaxants.
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PMID:Effects of adrenaline, isoprenaline and forskolin on pregnant human myometrial preparations. 327 33


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